Autocrine Transforming Growth Factor-β Signaling Promotes Cell Motility and Chemokine Secretion in an Angiomyolipoma-Derived Cell Model of Lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is a rare systemic disease that affects young women and is classified as a low-grade metastasizing neoplasm. It is characterized by uncontrolled proliferation of LAM cells within the lung parenchyma, which results from loss-of-function mutations in tuberous sclerosis complex 2 (TSC2) or 1 (TSC1) and activation of the mechanistic target of rapamycin complex 1. Abnormal cell growth leads to cyst formation and lung damage. Rapamycin-based therapy is the only approved treatment. Although it stabilizes the lung function in most patients, it has several limitations. Therefore, new therapeutic strategies are needed. This study examined the role of transforming growth factor-(3 (TGF-(3), a pleiotropic cytokine with well-established protumorigenic activity, in LAM cell biology. Using a TSC2-deficient angiomyolipoma-derived cell line indicated that TSC2-/- cells exhibited a higher expression of TGFb1 and TGFb3 than cells with restored TSC2 expression. Additionally, TSC2-/- cells expressed glycoprotein-A repetitions predominant and integrin (38, which promote TGF-(3 activation. Inhibition of TGF-( signaling in TSC2-/- cells reduced their migration in a wound healing assay, impaired transmigration through a threedimensional matrix, and decreased the expression of monocyte chemoattractant protein-1. These findings provide new insights into the regulation of processes contributing to LAM progression and point to TGF-(3 as one of the potential targets for LAM treatment. (Am J Pathol 2025, 195:1394-1410; https://doi.org/ 10.1016/j.ajpath.2025.04.019)